Viral conjunctivitis, known commonly as pink eye, is a common highly contagious disease Peristalsis is the distinctive pattern of smooth muscle contractions that propel foodstuffs distally through the esophagus and intestines. First described by Bayliss and Starling (J. Physio (Lond) 24:99-143, 1899) as a form of motility in which there is contraction above and relaxation below a segment being stimulated, it is unaffected by vagotomy or sympathectomy, indicating its mediation by the intestine's local, intrinsic nervous system. Peristalsis is a manifestation of two major reflexes within the enteric nervous system that are stimulated by a bolus of foodstuff in the lumen; mechanical distension and perhaps mucosal irritation stimulate afferent enteric neurons. These sensory neurons synapse with two sets of cholinergic interneurons, which leads to two distinct effects: one group of interneurons activates excitatory motor neurons above the bolus. These neurons, which can release acetylcholine and substance P, stimulate contraction of smooth muscle above the food bolus. Another group of interneurons activates inhibitory motor neurons that stimulate relaxation of smooth muscle below the bolus. These inhibitor neurons appear to use nitric oxide, vasoactive intestinal peptide and ATP as neurotransmitters.
Esophageal spasms are an uncoordinated series of muscle contractions that prevent food from traveling properly from the esophagus to the stomach. These spasms can be very painful, with chest pain a common symptom. Broadly, esophageal spasm can be subdivided into 2 distinct entities: diffuse esophageal spasm (DES), in which contractions are uncoordinated, and nutcracker esophagus, in which contractions proceed in a coordinated manner, but the amplitude is excessive. Symptoms can include dysphagia, regurgitation, and noncardiac chest pain. Because of the vague symptoms and difficulty in diagnosis, esophageal spasm is often undiagnosed and under-treated. Many patients with manometric and radiologic aberrations may not display any appreciable symptoms. Currently, manometry is the best diagnostic modality. Treatment includes calcium channel blockers, botulinum toxin, nitrates, tricyclic antidepressants, dilatation, myotomy, and esophagectomy.
Pathophysiology
The esophagus is comprised of 2 layers of muscle, the inner circular and the outer longitudinal layers. Arbitrarily, the esophagus can be divided into 3 zones, each with separate yet integrated anatomy and physiology.
Esophageal Zones
Upper zone: Comprised entirely of striated muscle, this zone initiates the contractions that propel the food bolus down the esophagus. The upper esophageal sphincter (UES; the cricopharyngeus muscle), is located in the upper zone. When functioning properly, the esophagus can detect the presence of a food bolus at the UES and then coordinate progression of the food down the esophagus to the stomach. When this does not occur in a coordinated fashion, the patient can develop symptoms of esophageal spasm. The UES is contracted tonically. Manometric evaluation of the UES reveals constant spiking activity. As food is sensed at the UES, the laryngeal muscles contract to move the cricoid cartilage anteriorly. The tonic contraction of the UES is inhibited, opening the UES to allow passage of food. The inner circular muscles and longitudinal muscles of the remainder of the upper zone then propel the food. To accomplish this, the longitudinal muscles must contract, followed immediately by contraction of the circular muscles. At the end of the upper zone, the initial wave dies out as another wave starts, propelling the food down to the middle zone. The nucleus solitarius in the brainstem controls swallowing in the upper zone.
Middle zone: Comprised of striated and smooth muscles, the inner circular muscle layer and the outer longitudinal muscle layer work in conjunction to propel the food bolus. The middle zone propels the food bolus from the upper zone to the lower zone. This segment consists of 2 muscle layers, an inner circular and outer longitudinal layer. Within the middle zone the striated muscle transitions to smooth, or involuntary, muscle. The wave propagates down the esophagus by coordinated contractions. Again, the longitudinal muscles must contract before the circular muscle contracts. Furthermore, contraction of the muscles must proceed caudally in an organized manner. If the muscle contraction is not orderly, the food bolus cannot progress. Gravity pulls the food caudally in concert with the organized contractions of the muscles.
Lower zone: The lower segment is known as the lower esophageal sphincter (LES), a thickening of the smooth muscle that is contracted tonically to prevent reflux. At rest, the pressure in the LES is usually 15-25 mm Hg. For food to pass into the stomach, the LES relaxes. Tonically, this muscle is contracted and must relax to allow food to pass. Failure of the LES to relax to allow a food bolus to pass is termed achalasia.
Diffuse Esophageal Spasm (DES)
Simplistically, DES occurs when the propagative waves do not progress correctly. Usually, several segments of the esophagus contract simultaneously, preventing the propagation of the food bolus. The usual presentation is intermittent dysphagia with occasional chest pain. Myotomy, which is performed only in extreme cases, can relieve the uncoordinated contractions.
Nutcracker Esophagus
Nutcracker esophagus occurs when the amplitude of the contractions exceeds 2 standard deviations from normal. The contractions proceed in an organized manner, propelling food down the esophagus. These patients often present with chest pain, but they present with dysphagia less often than patients with DES. Because the progression of the contractions occurs normally, patients often do not benefit from a myotomy. Even though the increased amplitude of the contractions can be demonstrated using manometry, the symptoms often do not correlate with the manometrically documented contractions. The symptoms of DES and nutcracker esophagus may overlap and can be distinguished only by motility study.
Imaging Studies
Barium swallow has proven useful in the diagnosis of esophageal spasm—DES has a characteristic appearance of multiple simultaneous contractions. This is often referred-to as a corkscrew appearance. Unlike in DES, barium swallow results for nutcracker esophagus are not specific.
Nino-Murcia and colleagues demonstrated thickening of the esophagus with CT scan studies in patients with esophageal spasm. Muscular hypertrophy has been documented in some patients with DES and nutcracker esophagus. The hypertrophy of the muscle wall is the cause of the increased thickness that is observed on CT scan images. The normal thickness of the esophagus is less than 3 mm. Many other disease processes, including malignancy, cause thickening of the esophagus that can be seen radiographically. Thus, thickening of the esophagus seen on CT scan images should prompt further workup. Even in patients with symptoms consistent with esophageal spasm, thickening seen on CT scan images should not be dismissed as muscular hypertrophy secondary to the esophageal spasms without further investigation.
Catheter-based high-frequency intraluminal ultrasound imaging assesses both the sensory function and the motor function of the esophagus. This imaging modality may be useful to distinguish between DES, nutcracker esophagus, and achalasia.
Manometry is the best modality to help diagnose DES. The classic definition is more than 2 uncoordinated contractions during 10 consecutive wet swallows (20% simultaneous esophageal contractions during standardized stationary motility testing). At least one peristaltic contraction must be present. Artificial neural networks may be useful in the recognition and objective classification of primary esophageal motor disorders investigated with stationary esophageal manometry recordings.
Increased release of acetylcholine appears to be a factor in DES, but the triggering event is not known. Other theories include gastric reflux or a primary nerve or motor disorder. Microvascular compression of the Vagus nerve in the brainstem has been demonstrated in current research as the possible triggering event. Medical therapy may focus on these blood vessels instead of on the muscles in the esophagus.
Medical and surgical options are available for the treatment of DES and nutcracker esophagus and have been used with moderate success. Medical treatment typically consists of calcium channel blockers, tricyclic antidepressants, nitrates, botulinum toxin, and dilatation. These conditions are usually not progressive but may interfere with the patient's quality of life. Calcium channel blockers can reduce the amplitude of the contractions. In patients with nutcracker esophagus, calcium channel blockers effectively reduce the amplitude of the contractions, but may not lessen chest pain. Traditionally, calcium channel blockers were thought to decrease the contractions. Nitrates also have been used with some success. The mechanism of action is unknown but may be related to decreasing vasospasm in the brainstem, similar to calcium channel blockers. Some patients benefit from sublingual nitroglycerin for acute symptoms of esophageal spasm.
Tricyclic antidepressants, specifically imipramine, have been shown to decrease chest pain with no apparent cause on angiogram. Studies specifically evaluating nutcracker esophagus are not yet available.
For extreme cases, operative treatment usually involves a myotomy. Myotomy relieves symptoms by eliminating the effectiveness of the contractions. The myotomy should extend the entire length of the involved segment, which should be determined preoperatively with manometry. Furthermore, the myotomy should extend through the LES to help prevent dysphagia postoperatively by preventing outlet obstruction. Finally, an antireflux procedure should be performed concomitantly.
Myotomy should be used with caution in patients with nutcracker esophagus because it may worsen the symptoms. Myotomy reduces the amplitude of the contractions, but this does not consistently improve symptoms, especially if the primary complaint is pain. Furthermore, dysphagia can develop or worsen after myotomy because the effectiveness of the propagative waves is eliminated, leaving gravity to propel food caudally. As a last resort, esophagectomy can be used to relieve symptoms. The esophagus is resected, and the stomach, small intestine, or colon is used to restore the continuity of the GI tract. Morbidity and mortality of esophagectomy are substantial; therefore, this should be performed only after other treatments have been exhausted.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of botulinum toxin type A (available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX®) is an LD50 in mice. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G, each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. The botulinum toxins apparently bind with high affinity to cholinergic motor neurons, are translocated into the neuron and block the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. Botulinum toxin type A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, hemifacial spasm, cervical dystonia, and migraine headaches. Botulinum toxin type B has also been approved by the FDA for the treatment of cervical dystonia. Clinical effects of peripheral intramuscular Botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of Botulinum toxin type A averages about three months.
It has been reported that Botulinum toxin type A has been used in clinical settings as follows:
about 75-125 U (U) of BOTOX® per intramuscular injection (multiple muscles) to treat cervical dystonia;
5-10 U of BOTOX® per intramuscular injection to treat glabellar lines (brow furrows) (5 U injected intramuscularly into the procerus muscle and 10 U injected intramuscularly into each corrugator supercilii muscle);
about 30-80 U of BOTOX® to treat constipation by intrasphincter injection of the puborectalis muscle;
about 1-5 U per muscle of intramuscularly injected BOTOX® to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 U of BOTOX®, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. the amount of diopter correction desired).
to treat upper limb spasticity following stroke by intramuscular injections of BOTOX® into five different upper limb flexor muscles, as follows:
(a) flexor digitorum profundus: 7.5 U to 30 U
(b) flexor digitorum sublimis: 7.5 U to 30 U
(c) flexor carpi ulnaris: 10 U to 40 U
(d) flexor carpi radialis: 15 U to 60 U
(e) biceps brachii: 50 U to 200 U.
Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX® by intramuscular injection at each treatment session.
To treat migraine, pericranial (symmetrically into glabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX® has showed significant benefit as a prophylactic treatment compared to vehicle as measured by decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the three month period following the 25 U injection.
Additionally, intramuscular Botulinum toxin has been used in the treatment of tremor in patients with Parkinson's disease, although it has been reported that results have not been impressive. Marjama-Jyons, J., et al., Tremor-Predominant Parkinson's Disease, Drugs & Aging 16(4); 273-278:2000.
In addition to having pharmacologic actions at the peripheral location, botulinum toxins may also have inhibitory effects in the central nervous system. Work by Weigand et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1976; 292, 161-165, and Habermann, Naunyn-Schmiedeberg's Arch. Pharmacol. 1974; 281, 47-56 showed that Botulinum toxin is able to ascend to the spinal area by retrograde transport. As such, a Botulinum toxin injected at a peripheral location, for example intramuscularly, may be retrograde transported to the spinal cord.
U.S. Pat. No. 5,989,545 discloses that a modified Clostridial neurotoxin or fragment thereof, preferably a Botulinum toxin, chemically conjugated or recombinantly fused to a particular targeting moiety can be used to treat pain by administration of the agent to the spinal cord.
A Botulinum toxin has also been proposed for the treatment of rhinorrhea, hyperhidrosis and other disorders mediated by the autonomic nervous system (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat. No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468), post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), pain treatment by intraspinal toxin administration (U.S. Pat. No. 6,113,915), Parkinson's disease and other diseases with a motor disorder component, by intracranial toxin administration (U.S. Pat. No. 6,306,403), hair growth and hair retention (U.S. Pat. No. 6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. no. 6,423,319, various cancers (U.S. Pat. No. 6,139,845), pancreatic disorders (U.S. Pat. No. 6,143,306), smooth muscle disorders (U.S. Pat. No. 5,437,291, including injection of a botulinum toxin into the upper and lower esophageal, pyloric and anal sphincters)), prostate disorders (U.S. Pat. No. 6,365,164), inflammation, arthritis and gout (U.S. Pat. No. 6,063,768), juvenile cerebral palsy (U.S. Pat. No. 6,395,277), inner ear disorders (U.S. Pat. No. 6,265,379), thyroid disorders (U.S. Pat. No. 6,358,513), parathyroid disorders (U.S. Pat. No. 6,328,977). Additionally, controlled release toxin implants are known (see e.g. U.S. Pat. Nos. 6,306,423 and 6,312,708).